Diabetic retinopathy (DR) has classically been regarded as a disease of the retinal microvasculature, and the natural history of the disease has been divided into an early, nonproliferative (or background) stage, and a later proliferative stage. These vascular lesions are largely responsible for the visual impairment/loss in advanced DR, and have been the focus of clinical trials to date. Though visual dysfunction and loss are less specific for diabetes, approval for therapies against DR from the FDA is based on therapies inhibiting these parameters in diabetic patients.
Vascular lesions in the early stages of DR in patients and animals are characterized histologically by the presence of obliterated and degenerated capillaries and pericyte-deficient capillaries. Capillary non-perfusion and degeneration are generally thought to play major roles in the progression to pre-retinal neovascularization that develops in some diabetic patients. As more capillaries become non-perfused or occluded, local areas of the retina likely become deprived of oxygen and nutrients, thus stimulating the production of one or more ischemia-driven growth factors (such as vascular endothelial growth factor (VEGF)) and the subsequent neovascular response. Progressive growth of abnormal vessels into the vitreous in proliferative DR (PDR) can lead to vitreous hemorrhage, pre-retinal hemorrhage, and eventually even to retinal detachment. Anti-VEGF therapies appear to inhibit or even reverse retinal neovascularization, with additional studies ongoing.
Increased vascular permeability is another alteration that leads to visual impairment in patients. Retinal edema seems to arise primarily from well-defined microaneurysms, but animal studies suggest that the leakage is more wide-spread. The pathophysiology of the edema apparently involves dilated capillaries, retinal microaneurysms, and impairment of the blood-retinal barrier, resulting in leakage of fluid into the extracellular space, thus disrupting macular structure and function. Diabetic macular edema (DME), defined as retinal edema involving or threatening the macula, is the most common cause of visual loss in DR. Whether the permeability defect is the only factor causing retinal edema in diabetes is unclear. Laser photocoagulation, anti-VEGF therapies, and steroids all can inhibit retinal edema in diabetes, although pharmacological approaches act only temporarily, and in about half of patients with DME.
Diabetes also results in dysfunction and degeneration of retinal neural cells. Loss of ganglion cells has been detected in diabetic rats and humans, but results in mice are controversial. Retinal electrophysiological abnormalities in diabetes include changes in ERGs, visual evoked potentials (VEPs), and subnormal oscillatory potential amplitudes. Recent clinical studies showed that inner and outer retinal function were impaired even during early (nonproliferative) stages of DR. Diabetes also impairs visual psychophysics, as evidenced by reductions in visual acuity, contrast sensitivity and color vision.